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1.
Nature ; 604(7905): 298-303, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1795722

ABSTRACT

Achiral sulfur functional groups, such as sulfonamide, sulfone, thiol and thioether, are common in drugs and natural products. By contrast, chiral sulfur functional groups are often neglected as pharmacophores1-3, although sulfoximine, with its unique physicochemical and pharmacokinetic properties4,5, has been recently incorporated into several clinical candidates. Thus, other sulfur stereogenic centres, such as sulfinate ester, sulfinamide, sulfonimidate ester and sulfonimidamide, have started to attract attention. The diversity and complexity of these sulfur stereogenic centres have the potential to expand the chemical space for drug discovery6-10. However, the installation of these structures enantioselectively into drug molecules is highly challenging. Here we report straightforward access to enantioenriched sulfinate esters via asymmetric condensation of prochiral sulfinates and alcohols using pentanidium as an organocatalyst. We successfully coupled a wide range of sulfinates and bioactive alcohols stereoselectively. The initial sulfinates can be prepared from existing sulfone and sulfonamide drugs, and the resulting sulfinate esters are versatile for transformations to diverse chiral sulfur pharmacophores. Through late-stage diversification11,12 of celecoxib and other drug derivatives, we demonstrate the viability of this unified approach towards sulfur stereogenic centres.


Subject(s)
Esters , Sulfur , Alcohols , Celecoxib , Stereoisomerism , Sulfonamides
2.
Org Lett ; 24(4): 995-999, 2022 02 04.
Article in English | MEDLINE | ID: covidwho-1655437

ABSTRACT

Thapsigargin (Tg) is a potent SERCA pump inhibitor with the potential to treat cancer and COVID-19. We have extended the scope of the asymmetric allenic Pauson-Khand reaction to furan-tethered allene-ynes, a stereoconvergent transformation affording the 5,7,5-ring system of Tg in good yields and high enantioselectivity. Computational studies of the oxidative cyclization step show that the furan and chloroacetate groups contribute to this high selectivity.


Subject(s)
Rhodium/chemistry , Thapsigargin/analogs & derivatives , Thapsigargin/chemistry , COVID-19/drug therapy , Catalysis , Chloroacetates/chemistry , Cyclization , Furans/chemistry , Models, Molecular , Molecular Structure , Stereoisomerism , Thapsia/chemistry
3.
Molecules ; 27(2)2022 Jan 17.
Article in English | MEDLINE | ID: covidwho-1635108

ABSTRACT

The design of novel nucleoside triphosphate (NTP) analogues bearing an all-carbon quaternary center at C2' or C3' is described. The construction of this all-carbon stereogenic center involves the use of an intramoleculer photoredox-catalyzed reaction. The nucleoside analogues (NA) hydroxyl functional group at C2' was generated by diastereoselective epoxidation. In addition, highly enantioselective and diastereoselective Mukaiyama aldol reactions, diastereoselective N-glycosylations and regioselective triphosphorylation reactions were employed to synthesize the novel NTPs. Two of these compounds are inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, the causal virus of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Carbon/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Nucleotides/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/enzymology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Nucleotides/chemical synthesis , Nucleotides/chemistry , SARS-CoV-2/drug effects , Stereoisomerism
4.
J Med Chem ; 64(24): 17846-17865, 2021 12 23.
Article in English | MEDLINE | ID: covidwho-1555306

ABSTRACT

The COVID-19 pandemic is having a major impact on public health worldwide, and there is an urgent need for the creation of an armamentarium of effective therapeutics, including vaccines, biologics, and small-molecule therapeutics, to combat SARS-CoV-2 and emerging variants. Inspection of the virus life cycle reveals multiple viral- and host-based choke points that can be exploited to combat the virus. SARS-CoV-2 3C-like protease (3CLpro), an enzyme essential for viral replication, is an attractive target for therapeutic intervention, and the design of inhibitors of the protease may lead to the emergence of effective SARS-CoV-2-specific antivirals. We describe herein the results of our studies related to the application of X-ray crystallography, the Thorpe-Ingold effect, deuteration, and stereochemistry in the design of highly potent and nontoxic inhibitors of SARS-CoV-2 3CLpro.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Chlorocebus aethiops , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/metabolism , Drug Design , HEK293 Cells , Humans , Hydrogen Bonding , Microbial Sensitivity Tests , Molecular Structure , Protein Binding , SARS-CoV-2/enzymology , Stereoisomerism , Vero Cells
5.
Eur J Pharmacol ; 915: 174670, 2022 Jan 15.
Article in English | MEDLINE | ID: covidwho-1549763

ABSTRACT

Hydroxychloroquine (HCQ) is a derivative of the antimalaria drug chloroquine primarily prescribed for autoimmune diseases. Recent attempts to repurpose HCQ in the treatment of corona virus disease 2019 has raised concerns because of its propensity to prolong the QT-segment on the electrocardiogram, an effect associated with increased pro-arrhythmic risk. Since chirality can affect drug pharmacological properties, we have evaluated the functional effects of the R(-) and S(+) enantiomers of HCQ on six ion channels contributing to the cardiac action potential and on electrophysiological parameters of isolated Purkinje fibers. We found that R(-)HCQ and S(+)HCQ block human Kir2.1 and hERG potassium channels in the 1 µM-100 µM range with a 2-4 fold enantiomeric separation. NaV1.5 sodium currents and CaV1.2 calcium currents, as well as KV4.3 and KV7.1 potassium currents remained unaffected at up to 90 µM. In rabbit Purkinje fibers, R(-)HCQ prominently depolarized the membrane resting potential, inducing autogenic activity at 10 µM and 30 µM, while S(+)HCQ primarily increased the action potential duration, inducing occasional early afterdepolarization at these concentrations. These data suggest that both enantiomers of HCQ can alter cardiac tissue electrophysiology at concentrations above their plasmatic levels at therapeutic doses, and that chirality does not substantially influence their arrhythmogenic potential in vitro.


Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Heart/drug effects , Hydroxychloroquine/chemistry , Hydroxychloroquine/pharmacology , Ion Channels/drug effects , Action Potentials/drug effects , Animals , Arrhythmias, Cardiac/chemically induced , Electrocardiography , Electrophysiologic Techniques, Cardiac , Ether-A-Go-Go Potassium Channels , Humans , Membrane Potentials/drug effects , Patch-Clamp Techniques , Purkinje Fibers/drug effects , Rabbits , Stereoisomerism
6.
Angew Chem Int Ed Engl ; 61(11): e202114619, 2022 03 07.
Article in English | MEDLINE | ID: covidwho-1544209

ABSTRACT

Since early 2020, scientists have strived to find an effective solution to fight SARS-CoV-2, in particular by developing reliable vaccines that inhibit the spread of the disease and repurposing drugs for combatting its effects on the human body. The antiviral prodrug Remdesivir is still the most widely used therapeutic during the early stages of the infection. However, the current synthetic routes rely on the use of protecting groups, air-sensitive reagents, and cryogenic conditions, thus impeding a cost-efficient supply to patients. We have, therefore, focused on the development of a straightforward, direct addition of (hetero)arenes to unprotected sugars. Here we report a silylium-catalyzed and completely stereoselective C-glycosylation that initially yields the open-chain polyols, which can be selectively cyclized to provide either the kinetic α-furanose or the thermodynamically favored ß-anomer. The method significantly expedites the synthesis of Remdesivir precursor GS-441524 after a subsequent Mn-catalyzed C-H oxidation and deoxycyanation.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Adenosine/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/chemical synthesis , Nucleosides/chemical synthesis , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine Monophosphate/chemical synthesis , Adenosine Monophosphate/chemistry , Alanine/chemical synthesis , Alanine/chemistry , Antiviral Agents/chemistry , COVID-19/drug therapy , Catalysis , Chemistry Techniques, Synthetic/economics , Chemistry Techniques, Synthetic/methods , Cyclization , Glycosylation , Humans , Models, Molecular , Nucleosides/chemistry , Stereoisomerism , Time Factors
7.
Bioorg Med Chem ; 53: 116523, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1525708

ABSTRACT

Since the end of 2019, the outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic. There is an urgent need for effective and low-toxic antiviral drugs to remedy Remdesivir's limitation. Hydroxychloroquine, a broad spectrum anti-viral drug, showed inhibitory activity against SARS-CoV-2 in some studies. Thus, we adopted a drug repurposing strategy, and further investigated hydroxychloroquine. We obtained different configurations of hydroxychloroquine side chains by using chiral resolution technique, and successfully furnished R-/S-hydroxychloroquine sulfate through chemical synthesis. The R configuration of hydroxychloroquine was found to exhibit higher antiviral activity (EC50 = 3.05 µM) and lower toxicity in vivo. Therefore, R-HCQ is a promising lead compound against SARS-CoV-2. Our research provides new strategy for the subsequent research on small molecule inhibitors against SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Hydroxychloroquine/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/toxicity , Chlorocebus aethiops , Drug Repositioning , Female , Hydroxychloroquine/chemical synthesis , Hydroxychloroquine/toxicity , Male , Mice , Microbial Sensitivity Tests , Stereoisomerism , Vero Cells
8.
J Sep Sci ; 45(2): 456-467, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1499288

ABSTRACT

Chloroquine and hydroxychloroquine have been studied since the early clinical treatment of SARS-CoV-2 outbreak. Considering these two chiral drugs are currently in use as the racemate, high-expression angiotensin-converting enzyme 2 cell membrane chromatography was established for investigating the differences of two paired enantiomers binding to angiotensin-converting enzyme 2 receptor. Molecular docking assay and detection of SARS-CoV-2 spike pseudotyped virus entry into angiotensin-converting enzyme 2-HEK293T cells were also conducted for further investigation. Results showed that each single enantiomer could bind well to angiotensin-converting enzyme 2, but there were differences between the paired enantiomers and corresponding racemate in frontal analysis. R-Chloroquine showed better angiotensin-converting enzyme 2 receptor binding ability compared to S-chloroquine/chloroquine (racemate). S-Hydroxychloroquine showed better angiotensin-converting enzyme 2 receptor binding ability than R-hydroxychloroquine/hydroxychloroquine. Moreover, each single enantiomer was proved effective compared with the control group; compared with S-chloroquine or the racemate, R-chloroquine showed better inhibitory effects at the same concentration. As for hydroxychloroquine, R-hydroxychloroquine showed better inhibitory effects than S-hydroxychloroquine, but it slightly worse than the racemate. In conclusion, R-chloroquine showed better angiotensin-converting enzyme 2 receptor binding ability and inhibitory effects compared to S-chloroquine/chloroquine (racemate). S-Hydroxychloroquine showed better angiotensin-converting enzyme 2 receptor binding ability than R-hydroxychloroquine/hydroxychloroquine (racemate), while the effect of preventing SARS-CoV-2 pseudovirus from entering cells was weaker than R-hydroxychloroquine/hydroxychloroquine (racemate).


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/drug effects , Chloroquine/chemistry , Chloroquine/pharmacology , Chromatography, High Pressure Liquid/methods , Hydroxychloroquine/chemistry , Hydroxychloroquine/pharmacology , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Cell Membrane/chemistry , Cell Membrane/drug effects , Cell Membrane/virology , HEK293 Cells , Humans , In Vitro Techniques , Molecular Docking Simulation , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/chemistry , Receptors, Virus/drug effects , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Solvents , Stereoisomerism , Virus Internalization
9.
Molecules ; 26(21)2021 Oct 26.
Article in English | MEDLINE | ID: covidwho-1488675

ABSTRACT

In the last two years, nucleosides analogues, a class of well-established bioactive compounds, have been the subject of renewed interest from the scientific community thanks to their antiviral activity. The COVID-19 global pandemic, indeed, spread light on the antiviral drug Remdesivir, an adenine C-nucleoside analogue. This new attention of the medical community on Remdesivir prompts the medicinal chemists to investigate once again C-nucleosides. One of the essential building blocks to synthetize these compounds is the D-(+)-ribono-1,4-lactone, but some mechanistic aspects linked to the use of different carbohydrate protecting groups remain unclear. Here, we present our investigations on the use of benzylidene as a ribonolactone protecting group useful in the synthesis of C-purine nucleosides analogues. A detailed 1D and 2D NMR structural study of the obtained compounds under different reaction conditions is presented. In addition, a molecular modeling study at the B3LYP/6-31G* level of theory with the SM8 solvation model for CHCl3 and DMSO to support the obtained results is used. This study allows for clarifying mechanistic aspects as the side reactions and structural rearrangements liked to the use of the benzylidene protecting group.


Subject(s)
Benzylidene Compounds/chemistry , Lactones/chemistry , Nucleosides/chemical synthesis , Ribose/analogs & derivatives , Adenine/analogs & derivatives , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/prevention & control , Humans , Lactones/chemical synthesis , Magnetic Resonance Spectroscopy , Models, Molecular , Nucleosides/metabolism , Purine Nucleosides , Ribose/chemical synthesis , Ribose/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Stereoisomerism
10.
Molecules ; 26(18)2021 Sep 12.
Article in English | MEDLINE | ID: covidwho-1410349

ABSTRACT

Chemical and biological investigation of the Madagascar endemic plant Saldinia proboscidea led to the isolation of an isomer of artemisinin, (-)-6-epi-artemisinin (2). Its structure was elucidated using a combination of NMR and mass spectrometry. The absolute configuration was established by chemical syntheses of compound 2 as well as a new stereoisomer (3). The comparable bioactivities of artemisinin (1) and its isomer (-)-6-epi-artemisinin (2) revealed that this change in configuration was not critical to their biological properties. Bioactivity was assessed using an apoptosis induction assay, a SARS-CoV-2 inhibitor assay, and a haematin polymerization inhibitory activity (HPIA) assay. This is the first report of an artemisinin-related compound from a genus not belonging to Artemisia and it is the first isolation of an artemisinin-related natural product that is the opposite enantiomeric series relative to artemisinin from Artemisia annua.


Subject(s)
Antimalarials/chemistry , Artemisinins/chemistry , Plant Extracts/chemistry , Rubiaceae/chemistry , Madagascar , Stereoisomerism
11.
J Am Soc Mass Spectrom ; 32(4): 1116-1125, 2021 Apr 07.
Article in English | MEDLINE | ID: covidwho-1397839

ABSTRACT

The metabolism of vitamin D3 includes a parallel C-3 epimerization pathway-in addition to the standard metabolic processes for vitamin D3-reversing the stereochemical configuration of the -OH group at carbon-3 (ß→α). While the biological function of the 3α epimer has not been elucidated yet, the additional species cannot be neglected in the analytical determination of vitamin D3, as it has the potential to introduce analytical errors if not properly accounted for. Recently, some inconsistent mass spectral behavior was seen for the 25-hydroxyvitamin D3 (25(OH)D3) epimers during quantification using electrospray LC-MS/MS. The present work extends that of Flynn et al. ( Ann. Clin. Biochem. 2014, 51, 352-559) and van den Ouweland et al. ( J. Chromatogr. B 2014, 967, 195-202), who reported larger electrospray ionization response factors for the 3α epimer of 25(OH)D3 in human serum samples as compared to the regular 3ß variant. The present work was concerned with the mechanistic reasons for these differences. We used a combination of electrospray ionization, atmospheric pressure chemical ionization, and density functional theory calculations to uncover structural dissimilarities between the epimers. A plausible mechanism is described based on intramolecular hydrogen bonding in the gas phase, which creates a small difference of proton affinities between the epimers. More importantly, this mechanism allows the explanation of the different ionization efficiencies of the epimers based on kinetic control of the ionization process, where ionization initially takes place at the hydroxyl group with subsequent proton transfer to a basic carbon atom. The barrier for this transfer differs between the epimers and is in direct competition with H2O elimination from the protonated hydroxyl group. The "hidden" site of high gas phase basicity was revealed through computational calculations and appears to be inaccessible via direct protonation.


Subject(s)
Calcifediol/blood , Chromatography, Liquid/methods , Tandem Mass Spectrometry/methods , Calcifediol/chemistry , Density Functional Theory , Gases , Molecular Structure , Protons , Solvents , Stereoisomerism
12.
Molecules ; 26(16)2021 Aug 22.
Article in English | MEDLINE | ID: covidwho-1376916

ABSTRACT

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a "two-bottle" as well as a "drinking in the dark" paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.


Subject(s)
Alcohol Drinking/pathology , Cannabinoid Receptor Antagonists/pharmacology , Endotoxemia/pathology , Ethanol/adverse effects , Nitric Oxide Synthase Type II/antagonists & inhibitors , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Alcohol Drinking/blood , Animals , Anxiety/blood , Anxiety/complications , Behavior, Animal/drug effects , Catalepsy/chemically induced , Catalepsy/complications , Cyclohexanols/administration & dosage , Elevated Plus Maze Test , Endotoxemia/blood , Endotoxemia/complications , Endotoxins/blood , Gastrointestinal Tract/drug effects , Gastrointestinal Tract/metabolism , Hypothermia, Induced , Mice, Inbred C57BL , Nitric Oxide Synthase Type II/metabolism , Pyrazoles/administration & dosage , Receptor, Cannabinoid, CB1/metabolism , Rimonabant/administration & dosage , Rimonabant/pharmacology , Stereoisomerism , Sulfonamides/administration & dosage
13.
Int J Mol Sci ; 22(15)2021 Jul 27.
Article in English | MEDLINE | ID: covidwho-1332900

ABSTRACT

A novel series of N-substituted cis- and trans-3-aryl-4-(diethoxyphosphoryl)azetidin-2-ones were synthesized by the Kinugasa reaction of N-methyl- or N-benzyl-(diethyoxyphosphoryl)nitrone and selected aryl alkynes. Stereochemistry of diastereoisomeric adducts was established based on vicinal H3-H4 coupling constants in azetidin-2-one ring. All the obtained azetidin-2-ones were evaluated for the antiviral activity against a broad range of DNA and RNA viruses. Azetidin-2-one trans-11f showed moderate inhibitory activity against human coronavirus (229E) with EC50 = 45 µM. The other isomer cis-11f was active against influenza A virus H1N1 subtype (EC50 = 12 µM by visual CPE score; EC50 = 8.3 µM by TMS score; MCC > 100 µM, CC50 = 39.9 µM). Several azetidin-2-ones 10 and 11 were tested for their cytostatic activity toward nine cancerous cell lines and several of them appeared slightly active for Capan-1, Hap1 and HCT-116 cells values of IC50 in the range 14.5-97.9 µM. Compound trans-11f was identified as adjuvant of oxacillin with significant ability to enhance the efficacy of this antibiotic toward the highly resistant S. aureus strain HEMSA 5. Docking and molecular dynamics simulations showed that enantiomer (3R,4S)-11f can be responsible for the promising activity due to the potency in displacing oxacillin at ß-lactamase, thus protecting the antibiotic from undesirable biotransformation.


Subject(s)
Adjuvants, Pharmaceutic/chemistry , Adjuvants, Pharmaceutic/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Azetidines/pharmacology , Infections/drug therapy , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Azetidines/chemistry , Bacterial Proteins/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Coronavirus 229E, Human/drug effects , Cytostatic Agents/chemistry , Cytostatic Agents/pharmacology , Humans , Influenza A Virus, H1N1 Subtype/drug effects , Molecular Dynamics Simulation , Oxacillin/chemistry , Penicillin-Binding Proteins/chemistry , Staphylococcus aureus/drug effects , Stereoisomerism , beta-Lactamases/chemistry
14.
Molecules ; 26(11)2021 May 31.
Article in English | MEDLINE | ID: covidwho-1323314

ABSTRACT

Dendrimers comprise a specific group of macromolecules, which combine structural properties of both single molecules and long expanded polymers. The three-dimensional form of dendrimers and the extensive possibilities for use of additional substrates for their construction creates a multivalent potential and a wide possibility for medical, diagnostic and environmental purposes. Depending on their composition and structure, dendrimers have been of interest in many fields of science, ranging from chemistry, biotechnology to biochemical applications. These compounds have found wide application from the production of catalysts for their use as antibacterial, antifungal and antiviral agents. Of particular interest are peptide dendrimers as a medium for transport of therapeutic substances: synthetic vaccines against parasites, bacteria and viruses, contrast agents used in MRI, antibodies and genetic material. This review focuses on the description of the current classes of dendrimers, the methodology for their synthesis and briefly drawbacks of their properties and their use as potential therapies against infectious diseases.


Subject(s)
Anti-Infective Agents/pharmacology , Communicable Diseases/drug therapy , Dendrimers/chemistry , Peptides/chemistry , Polymers/chemistry , Animals , Anti-HIV Agents/pharmacology , Bacterial Infections/drug therapy , Biotechnology , COVID-19/drug therapy , Catalysis , Contrast Media , Drug Delivery Systems , Drug Design , HIV Infections/drug therapy , Humans , Infectious Disease Medicine/trends , Magnetic Resonance Imaging , Mice , Nanotechnology , Polypropylenes/chemistry , SARS-CoV-2 , Stereoisomerism , Tomography, X-Ray Computed/trends , Virus Diseases/drug therapy
15.
Molecules ; 26(12)2021 Jun 16.
Article in English | MEDLINE | ID: covidwho-1282539

ABSTRACT

Furan-2-carboxylic acid was used as a starting material for the synthesis of dehydro-homopilopic acid. Esterification, hydrogenation and enzymatic hydrolysis followed by the reduction of Weinreb amides and a single-step attachment of a 1-methyl-imidazole residue allowed for the concise synthesis of both enantiomers of pilocarpine.


Subject(s)
4-Butyrolactone/analogs & derivatives , Furans/chemistry , Pilocarpine/chemical synthesis , 4-Butyrolactone/chemical synthesis , Amides/chemistry , Carboxylic Acids/chemistry , Esterification , Hydrogenation , Hydrolysis , Pilocarpine/chemistry , Stereoisomerism
16.
J Chem Theory Comput ; 17(7): 4578-4598, 2021 Jul 13.
Article in English | MEDLINE | ID: covidwho-1275856

ABSTRACT

The functional adaptability and conformational plasticity of SARS-CoV-2 spike proteins allow for the efficient modulation of complex phenotypic responses to the host receptor and antibodies. In this study, we combined atomistic simulations with mutational and perturbation-based scanning approaches to examine binding mechanisms of the SARS-CoV-2 spike proteins with three different classes of antibodies. The ensemble-based profiling of binding and allosteric propensities of the SARS-CoV-2 spike protein residues showed that these proteins can work as functionally adaptable and allosterically regulated machines. Conformational dynamics analysis revealed that binding-induced modulation of soft modes can elicit the unique protein response to different classes of antibodies. Mutational scanning heatmaps and sensitivity analysis revealed the binding energy hotspots for different classes of antibodies that are consistent with the experimental deep mutagenesis, showing that differences in the binding affinity caused by global circulating variants in spike positions K417, E484, and N501 are relatively moderate and may not fully account for the observed antibody resistance effects. Through functional dynamics analysis and perturbation-response scanning of the SARS-CoV-2 spike protein residues in the unbound form and antibody-bound forms, we examine how antibody binding can modulate allosteric propensities of spike protein residues and determine allosteric hotspots that control signal transmission and global conformational changes. These results show that residues K417, E484, and N501 targeted by circulating mutations correspond to a group of versatile allosteric centers in which small perturbations can modulate collective motions, alter the global allosteric response, and elicit binding resistance. We suggest that the SARS-CoV-2 S protein may exploit the plasticity of specific allosteric hotspots to generate escape mutants that alter the response to antibody binding without compromising the activity of the spike protein.


Subject(s)
Antibodies, Viral/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Antigen-Antibody Reactions , Antigens, Viral/chemistry , Binding Sites , Humans , Models, Molecular , Molecular Dynamics Simulation , Mutation/genetics , Protein Conformation , Spike Glycoprotein, Coronavirus/genetics , Stereoisomerism
17.
Chem Biol Drug Des ; 98(4): 604-619, 2021 10.
Article in English | MEDLINE | ID: covidwho-1273079

ABSTRACT

3CLpro is essential for SARS-CoV-2 replication and infection; its inhibition using small molecules is a potential therapeutic strategy. In this study, a comprehensive crystallography-guided fragment-based drug discovery approach was employed to design new inhibitors for SARS-CoV-2 3CLpro. All small molecules co-crystallized with SARS-CoV-2 3CLpro with structures deposited in the Protein Data Bank were used as inputs. Fragments sitting in the binding pocket (87) were grouped into eight geographical types. They were interactively coupled using various synthetically reasonable linkers to generate larger molecules with divalent binding modes taking advantage of two different fragments' interactions. In total, 1,251 compounds were proposed, and 7,158 stereoisomers were screened using Glide (standard precision and extra precision), AutoDock Vina, and Prime MMGBSA. The top 22 hits having conformations approaching the linear combination of their constituent fragments were selected for MD simulation on Desmond. MD simulation suggested 15 of these did adopt conformations very close to their constituent pieces with far higher binding affinity than either constituent domain alone. These structures could provide a starting point for the further design of SARS-CoV-2 3CLpro inhibitors with improved binding, and structures are provided.


Subject(s)
Antiviral Agents/chemistry , COVID-19/drug therapy , SARS-CoV-2/drug effects , Viral Protease Inhibitors/chemistry , Viral Proteases/metabolism , Antiviral Agents/pharmacology , Crystallization , Drug Design , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Multivariate Analysis , Protein Binding , Protein Conformation , Stereoisomerism , Structure-Activity Relationship , Viral Protease Inhibitors/pharmacology
18.
Sci Rep ; 11(1): 8017, 2021 04 13.
Article in English | MEDLINE | ID: covidwho-1182869

ABSTRACT

Hydroxychloroquine (2-[[4-[(7-Chloroquinolin-4-yl) amino]pentyl](ethyl) amino]-ethanol, HCQ), an effective anti-malarial drug, has been tested in the clinics for potential treatment of severe coronavirus disease 2019 (COVID-19). Despite the controversy around the clinical benefits of HCQ, the existence of a chiral center in the molecule to possess two optical isomers suggests that there might be an enantiomeric difference on the treatment of COVID-19. Due to their poor resolution and the inability of quantification by previously reported methods for the analysis of HCQ enantiomers, it is necessary to develop an analytical method to achieve baseline separation for quantitative and accurate determination of the enantiomeric purity in order to compare the efficacy and toxicity profiles of different enantiomers. In this study, we developed and validated an accurate and reproducible normal phase chiral high-performance liquid chromatography (HPLC) method for the analysis of two enantiomers of HCQ, and the method was further evaluated with biological samples. With this newly developed method, the relative standard deviations of all analytes were lower than 5%, and the limits of quantification were 0.27 µg/ml, 0.34 µg/ml and 0.20 µg/ml for racemate, R- and S-enantiomer, respectively. The present method provides an essential analytical tool for preclinical and clinical evaluation of HCQ enantiomers for potential treatment of COVID-19.


Subject(s)
Chromatography, High Pressure Liquid , Hydroxychloroquine/analysis , Animals , COVID-19/drug therapy , COVID-19/virology , Humans , Hydroxychloroquine/blood , Hydroxychloroquine/chemistry , Rats , Rats, Sprague-Dawley , Reproducibility of Results , SARS-CoV-2/isolation & purification , Stereoisomerism
19.
Angew Chem Int Ed Engl ; 60(3): 1605-1609, 2021 01 18.
Article in English | MEDLINE | ID: covidwho-1064320

ABSTRACT

A nickel-catalyzed asymmetric reductive hydroarylation of vinyl amides to produce enantioenriched α-arylbenzamides is reported. The use of a chiral bisimidazoline (BIm) ligand, in combination with diethoxymethylsilane and aryl halides, enables the regioselective introduction of aryl groups to the internal position of the olefin, forging a new stereogenic center α to the N atom. The use of neutral reagents and mild reaction conditions provides simple access to pharmacologically relevant motifs present in anticancer, SARS-CoV PLpro inhibitors, and KCNQ channel openers.


Subject(s)
Benzamides/chemical synthesis , Nickel/chemistry , Alkenes/chemistry , Catalysis , Imidazolines/chemistry , Molecular Conformation , Organosilicon Compounds/chemistry , Stereoisomerism , Thermodynamics
20.
Acta Crystallogr C Struct Chem ; 76(Pt 12): 1043-1050, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-1040909

ABSTRACT

The first example of molecular docking of the SARS-CoV-2 main protease for COVID-19 [Mpro, Protein Data Bank (PDB) code 7BQY] by a chalcone-based ligand, namely, (E)-1-(2,4-dichlorophenyl)-3-[4-(morpholin-4-yl)phenyl]prop-2-en-1-one, C19H17Cl2NO2, I, is presented. Two-dimensional (2D) LIGPLOT representations calculated for the inhibitor N3, viz. N-{[(5-methylisoxazol-3-yl)carbonyl]alanyl}-L-valyl-N1-((1R,2Z)-4-(benzyloxy)-4-oxo-1-{[(3R)-2-oxopyrrolidin-3-yl]methyl}but-2-enyl)-L-leucinamide, and 7BQY are included for comparison with our chalcone-based complexes. The binding affinity of our chalcone ligand with 7BQY is -7.0 kcal mol-1, a high value which was attributed to the presence of a hydrogen bond, together with many hydrophobic interactions between the drug and the active amino acid residues of the receptor. Docking studies were also performed, employing rigid and flexible binding modes for the ligand. The superposition of N3 and the chalcone docked into the binding pocket of 7BQY is also presented. The synthesis, single-crystal structure, Hirshfeld surface analysis (HSA) and spectral characterization of heterocyclic chalcone-based compound I, are also presented. The molecules are stacked, with normal π-π interactions, in the crystal.


Subject(s)
Antiviral Agents/metabolism , COVID-19/enzymology , Chalcones/metabolism , Coronavirus 3C Proteases/metabolism , SARS-CoV-2/enzymology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Catalytic Domain , Chalcones/chemical synthesis , Chalcones/chemistry , Coronavirus 3C Proteases/chemistry , Crystallography, X-Ray , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Molecular Docking Simulation , Oligopeptides/metabolism , Protein Binding , Stereoisomerism
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